Bisphosphonates (BPs) are potent inhibitors of bone resorption currently used in the treatment of osteoporosis, hypercalcemia of malignancy, multiple myeloma, and bone metastases associated with, breast, prostate, and lung cancer. In 2003, Marx reported 36 patients receiving intravenous BPs who developed unusual lesions of exposed bone in the jaws. Thirty five of these patients were concurrently receiving chemotherapy for cancer. Subsequently, Ruggiero et al. reported 63 patients with similar lesions of the jaws. In their series, 56 patients were under treatment for various malignancies and 7 patients were receiving therapy for osteoporosis. Intravenous BPs had been administered to all patients. Many, but not all patients had dental extractions or surgical manipulation prior to the development of osteonecrosis (ON). While it appears likely that an association of ON with BP therapy exists, scientifically-based studies are critical in order to define the pathogenesis and natural history of this condition. Although BPs is currently utilized in the treatment of a limited number of conditions, the potential for these drugs to be used in many other applications is vast. It is therefore critical to future patient care to identify risk factors and candidate markers for the development of jaw ON. This proposal will describe a case controlled, cross-sectional as well as a prospective longitudinal pilot study of a well defined group of breast cancer patients being treated with chemotherapy. The case controlled study will evaluate patients who present with ON. Age and ethnically matched patients without ON from the prospective study will be compared to affected patients in order to identify local and systemic abnormalities that are associated with this condition. The prospective study will examine two groups of 200 breast cancer patients on maintenance chemotherapy, with one group receiving BPs for the treatment of skeletal related events secondary to bone metastases. We will examine a number of risk factors including oral hygiene, the presence of dental disease, early radiographic findings, bone turnover, coagulopathies, depression of serum angiogenesis factors, and alteration of blood cells or serum chemistry to determine if we can predict which patients will develop this condition. The findings will be used to define the natural history, risk factors, and candidate markers for the development of jaw osteonecrosis and allow future development of rational prevention and treatment regimens. [unreadable] [unreadable] [unreadable]